TW200946504A - Improved process for the manufacture of 2,3-dichloropyridine - Google Patents
Improved process for the manufacture of 2,3-dichloropyridine Download PDFInfo
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- TW200946504A TW200946504A TW98107788A TW98107788A TW200946504A TW 200946504 A TW200946504 A TW 200946504A TW 98107788 A TW98107788 A TW 98107788A TW 98107788 A TW98107788 A TW 98107788A TW 200946504 A TW200946504 A TW 200946504A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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Description
200946504 六、發明說明： 【先前技術】 存在對製造2,3-二氣吡啶之高效且實用之方法的需要 2,3-二氣吼啶為製備作物保護劑、醫藥及其他精細。 、、 予品 之重要原料。 PCT專利公開案WO 2005/070888揭示2,3-二氣n比唆之製 備’其中在鹽酸水溶液存在下使3-胺基-2·氣吡唆與亞確酸 鹽接觸以形成重氮鹽’該重氮鹽隨後在鋼觸媒存在下八 ® 解。對於商業上大規模實施之重氮化反應，亞硝酸鹽之量 不能總得到精確控制，且因此通常使用過量（亦即，相對 於芳族胺大於化學計量配比）亞硝酸鹽來確保胺完全轉化 為重氮鹽。雖然WO 2005/070888中所揭示的方法當使用化 學計量配比（亦即，等莫耳）量之亞硝酸鹽得到高產率，但 利用過量亞硝酸鹽可導致重氮鹽分解步驟中之銅觸媒失 活。銅觸媒之失活可因重氮鹽改為熱水解成羥基吡啶副產 藝物而降低2,3 -二氣吼咬產物之產率。在大規模製造中甚至 更顯著，觸媒之失活可導致分解反應器中所產生之氮氣之 壓力延遲且突然增加。雖然由過量亞硝酸鹽所形成之殘餘 * 亞蝴酸可藉由在分解步驟之前向重氮溶液中添加諸如脲或 • 胺續酸之亞硝酸淨化劑來移除，但此可引起不可接受之氣 體逸出及液體發泡，從而產生過高壓力或溢出反應器。雖 然有意利用小於化學計量配比之量之亞硝酸鹽避免銅觸媒 失活’但此產生較低的2,3_二氣吡啶產率且殘留殘餘3-胺 基-2-氣"比。定，而殘餘3_胺基_2_氣吡啶必須加以分離且再 138804.doc 200946504 循環。至今尚未發現該問題的較佳解決方案。 【發明内容】 本發明係關於一種製備2,3-二氣吡啶（1)之方法200946504 VI. Description of the Invention: [Prior Art] There is a need for an efficient and practical method for producing 2,3-dipyridine. 2,3-dioxacridine is used for the preparation of crop protection agents, medicines and other fines. , and important raw materials for the product. PCT Patent Publication No. WO 2005/070888 discloses the preparation of 2,3-dioxane n-pyrene, wherein 3-amino-2-pyrazine is contacted with a hypo-acid salt to form a diazonium salt in the presence of aqueous hydrochloric acid. The diazonium salt is then decomposed in the presence of a steel catalyst. For commercially large-scale diazotization reactions, the amount of nitrite cannot always be precisely controlled, and therefore it is common to use an excess (i.e., greater than the stoichiometric ratio relative to the aromatic amine) nitrite to ensure complete amines. Conversion to diazonium salt. Although the process disclosed in WO 2005/070888 uses a stoichiometric (i.e., equimolar) amount of nitrite to achieve high yields, the use of excess nitrite can result in copper contact in the diazonium salt decomposition step. The media is inactivated. The inactivation of the copper catalyst can reduce the yield of the 2,3 - 2 gas bite product by changing the diazonium salt to thermal hydrolysis to a hydroxypyridine by-product. Even more pronounced in large scale manufacturing, the deactivation of the catalyst can result in a delayed and abrupt increase in the pressure of the nitrogen produced in the decomposition reactor. Although the residual *cyanic acid formed from excess nitrite can be removed by adding a nitrous acid scavenger such as urea or amine acid to the diazo solution prior to the decomposition step, this can cause unacceptable Gas escaping and liquid foaming, resulting in excessive pressure or spillage of the reactor. Although intentionally using less than the stoichiometric amount of nitrite to avoid copper catalyst deactivation 'but this yields lower 2,3_dioxidine yield and residual residual 3-amino-2-gas" . The residual 3_amino-2_pyridine must be separated and recirculated 138804.doc 200946504. No better solution to this problem has been found so far. SUMMARY OF THE INVENTION The present invention relates to a method for preparing 2,3-dioxapyridine (1)
其包含以下步驟： (1)使3-胺基-2-氣吼啶（2)或包含3-胺基_2_氣β比啶（2)之 溶液It comprises the following steps: (1) 3-amino-2- gas acridine (2) or a solution containing 3-amino-2_gas β-pyridine (2)
C1 與鹽酸接觸以形成3 -胺基-2 -氣η比咬鹽酸鹽； (2)使3-胺基-2-氯》比啶鹽酸鹽與亞硝酸鹽接觸以形成相 應的氣化重氮鹽；及 (3)在胺嶒酸及其中至少約5〇%之銅為鋼（^)氧化態之銅 觸媒存在下，視情況在有機溶劑存在下，使相應的氣化重 氮鹽與鹽酸接觸以形成2,3-二氣吡啶（1)。 【實施方式】 如本文中所使用，術語r包含」、「包括」、「具有 或「含有」或其任何其他變化意欲涵蓋非排他性包括。舉 例而言，包含一組元件之組合物、混合物、製程、方法、 物件或裳置不-定揭限於僅該等元件，而可包括其他未明 確列出或該組合物、混合物、製程、方法、物件或敦置所 138804.doc 200946504 固有之70件。另外，除非明確相反說明，否則「或」係指 包括性或且不是指排他性或。舉例而言，條件A或B滿足 以下各項中之任一項：A真（或存在）且B假（或不存在），A 假（或不存在）且B真（或存在）’及A及B均真（或存在）。 又，本發明之元件或組件前面的不定冠詞「一」不意欲 限制το件或組件之出現次數（亦即，出現率）。因此，C1 is contacted with hydrochloric acid to form a 3-amino-2- gas η ratio bite hydrochloride; (2) 3-amino-2-chloro" is contacted with pyridine salt to form a corresponding gasification a diazonium salt; and (3) in the presence of aminic citric acid and at least about 5% of the copper is in the presence of a copper catalyst in the oxidation state of the steel (^), optionally in the presence of an organic solvent, the corresponding gasified diazonium The salt is contacted with hydrochloric acid to form 2,3-dipyridine (1). [Embodiment] As used herein, the term "including", "including", "having" or "including" or any other variation thereof is intended to cover a non-exclusive. For example, a composition, mixture, process, method, article, or article comprising a group of elements is not limited to such elements, but may include other components, mixtures, processes, methods that are not explicitly listed. 70 items intrinsic to the object, or the 138804.doc 200946504. In addition, unless expressly stated to the contrary, "or" means inclusive or not exclusive. For example, condition A or B satisfies any of the following: A true (or existing) and B false (or non-existent), A false (or non-existent) and B true (or present) 'and A And B are true (or exist). Further, the indefinite article "a" or "an" or "an" or "an" or "an" or "an" is not intended to limit the number of occurrences (i.e., the rate of occurrence) of a component or component. therefore,
匕：」應視為包括一個或至少一個，且除非數字明顯意欲 才曰單數$則元件或組件之單數字組形式亦包括複數。 在本文中一些情況下’以單個數字列舉比率，該數字係 相對於數字1 ;例如，比率為4意謂4:1。 如本文中所提及’術語「莫耳當量」與化合物之化學活 性組分有關。舉例而言，在本發明方法之情況下，鹽酸之 莫耳當量係、指氣化氫之莫耳數（例如’相對於3胺基_2·氣 °比咬（2)之莫耳數。亞硝酸鹽之莫耳當量係指亞⑽根離子 之莫耳數（例如’相對於3_胺基·2·㈣蝴之莫耳數）。銅 觸媒之莫耳當量係指觸媒中銅、尤其銅⑴）之莫耳數（例 如相對於轉化為重氮鹽之胺基_2·氣κ (2)之莫耳 文中所提及’術語「標稱」如在諸如「標稱莫耳 比」之表述中所使用意謂近似。 、 本發明之實施例包括： 咬(：:1法如:發明發明内容中所陳述之製備2,3-二氣吼 二之方法，其中步驟⑴中之鹽酸(亦即氣化氮水溶液)與 基氣吡啶(2)之標稱莫耳比為至少約卜 138804.doc 200946504 實施例ΙΑ :實施例1之方法，其中步驟（1)中之鹽酸與3_ 胺基-2-氯吡啶（2)之標稱莫耳比為至少約2。 實施例1B :實施例1A之方法，其中步驟（丨）中之鹽酸與 3-胺基-2-氯吡啶（2)之標稱莫耳比為至少約3。 實施例1C :如本發明發明内容或實施例j至丨b中任一實 施例中所陳述之製備2,3-二氣吡啶（1)之方法，其中步驟（1) 中之鹽酸（亦即氣化虱水溶液）與3-胺基_2_氣η比唆（2)之標稱 莫耳比不超過約10。 實施例1D :實施例1C之方法，其中步驟（1)中之鹽酸與 3-胺基-2-氣吡啶（2)之標稱莫耳比不超過約6。 實施例2 :如本發明發明内容或實施例1至11)中任一實施 例中所陳述之製備2,3-二氣吡啶（1)之方法，其中步驟（3)中 之鹽酸（亦即氣化氫水溶液）與3·胺基_2_氯吡啶（2)之標稱莫 耳比為至少約1。 實施例2Α :如本發明發明内容或實施例i至⑴或2中任 一實她例中所陳述之製備2,3-二氣吡啶（j)之方法，其中步 驟（3)中之鹽酸（亦即氣化氯水溶液）與3胺基_2_氯吡啶 之標稱莫耳比不超過約1 〇。 實施例2B :如本發明發明内容或實施例2A中所陳述之 製備2,3_二氣吼咬⑴之方法，其中步驟⑺中之鹽酸與3_胺 基-2-氯"比咬（2)之標稱莫耳比不超過約5。 實施例3 :如本發明發明内容中所陳述之製備2，弘二氣吡 咬（1)之方法，彡中步驟（2)中之亞硝，酸鹽（以亞石肖酸根離子 之莫耳數計）與3·胺mtb咬（2)之標稱莫耳比為至少約 138804.docThe word "single" is intended to include the singular and the singular and the singular and singular. In some cases herein, the ratio is enumerated in a single number, which is relative to the number 1; for example, a ratio of 4 means 4:1. As used herein, the term "mole equivalent" relates to the chemically active component of a compound. For example, in the case of the method of the present invention, the molar equivalent of hydrochloric acid refers to the number of moles of hydrogenated hydrogen (for example, the number of moles relative to the 3 amine group 2 gas ratio bite (2). The molar equivalent of nitrite refers to the molar number of sub-(10) ions (for example, 'relative to the molar number of 3-amino-2·(4)). The molar equivalent of copper catalyst refers to copper in the catalyst. , in particular, the number of moles of copper (1) (for example, the term "nominal" as used in relation to the amines converted to the diazonium salt of the amine group 2 · gas κ (2), such as in the "nominal molar ratio" The expression used in the expression means approximation. The embodiment of the present invention comprises: a bite (::1 method such as: the method for preparing 2,3-dioxon 2 as stated in the invention, wherein the step (1) The nominal molar ratio of hydrochloric acid (i.e., aqueous vaporized nitrogen solution) to base gas pyridine (2) is at least about 138804.doc 200946504. Example: The method of Example 1, wherein the hydrochloric acid in step (1) is 3_ The nominal molar ratio of the amino-2-chloropyridine (2) is at least about 2. Example 1B: The method of Example 1A wherein the hydrochloric acid and 3-amino-2-chloropyridyl in the step (丨) (2) The nominal molar ratio is at least about 3. Example 1C: Preparation of 2,3-dioxapyridine (1) as set forth in any of the examples of the present invention or examples j to 丨b The method wherein the nominal molar ratio of hydrochloric acid (i.e., aqueous hydrazine hydrate solution) to 3-amino-2 气 η ratio 2 (2) in step (1) does not exceed about 10. Example 1D: Implementation The method of Example 1C, wherein the nominal molar ratio of hydrochloric acid to 3-amino-2-pyridine (2) in step (1) is no more than about 6. Example 2: According to the present invention or Example 1 The method for producing 2,3-dipyridyl (1) as recited in any one of the preceding embodiments, wherein the hydrochloric acid in step (3) (ie, an aqueous solution of hydrogenated hydrogen) and the 3 -amino group 2_ The nominal molar ratio of the chloropyridine (2) is at least about 1. Example 2: Preparation of 2,3-diox as set forth in the Summary of the Invention or in any of Examples i to (1) or 2 The method of pyridine (j), wherein the nominal molar ratio of hydrochloric acid (i.e., vaporized aqueous chlorine solution) to 3-amino-2-chloropyridine in step (3) does not exceed about 1 Torr. Example 2B: SUMMARY OF THE INVENTION or as set forth in Example 2A A method of preparing 2,3_two gas bites (1), wherein the nominal molar ratio of hydrochloric acid to 3-amino-2-chloro" to bite (2) in step (7) does not exceed about 5. Example 3: The method for preparing 2, Hong Erqi Pibit (1) as recited in the Summary of the Invention, the nitrous acid in the step (2), the acid salt (based on the molar number of the sulphate ion) and 3 The nominal molar ratio of the amine mtb bite (2) is at least about 138804.doc
200946504 0·95。 實施例3A :實施例3之方法，其中步驟（2)中之亞硝酸鹽 與3-胺基-2-氣吡啶（2)之標稱莫耳比為至少約i。 實施例3B :實施例3之方法，其中步驟（2)中之亞硝酸鹽 與3-胺基-2-氣吡啶（2)之標稱莫耳比為至少約1〇5。 實施例3C :如本發明發明内容或實施例3至3B中任一實 施例中所陳述之製備2,3_二氯_⑴之方法，#中步驟⑺ 中之亞硝酸鹽與3-胺基-2-氣吡啶（2)之標稱莫耳比（亦即亞 石肖酸鹽之莫耳當量與3_胺基m定之莫耳數之比）不超 過約2。 貝施例3D .實施例3C之方法，其中步驟⑺中之亞石肖酸 鹽與3-胺m㈣（2)之標稱莫耳比不超過。 實施例3E :如本發明發明内容或實施例3至31)中任一實 施例中所陳述之製備2 3 --患、 我侑，j 一氣吡啶（1)之方法，其中亞硝酸 鹽為亞硝酸鈉。 實施例4 :如本發明發明内容中所陳述之製備2,3-二氣吼 咬⑴之方法，其中銅觸媒中之銅與3·胺比咬⑺之 標稱莫耳比（亦即銅之莫耳當量與3_胺基_2_氣_之莫耳 數之比）為至少約〇.〇5。 實施例4 A :實施例4之方法 基-2-氣吼啶（2)之標稱莫耳比為 1其中銅觸媒中之銅與3-胺 至少約0.2。 實施例4B:如本發明發明内容或實施例4至4A中任一實 施例中所陳述之製備2,3_二氯^⑴之方法，纟中銅觸媒 中之銅與3·胺基.2_氣_(2)之標稱莫耳比不超過約2。 138804.doc 200946504 實施例4C :實施例4B之方法，其中銅觸媒中之銅與3-胺 基-2-氣吡啶（2)之標稱莫耳比不超過約0.6。 實施例5 :如本發明發明内容或實施例4至4 A中任一實施 例中所陳述之製備2,3-二氣吡啶（1)之方法，其中至少約 75%之銅呈銅（II)氧化態。 實施例5 A :實施例5之方法，其中至少約90%之銅呈銅 (II)氧化態。 實施例5B :實施例5 A之方法，其中至少約95%之銅呈銅 (II)氧化態。 實施例5C :實施例5B之方法，其中至少約99%之銅呈銅 (Π)氧化態。 實施例5D :實施例5C之方法，其中約1 〇〇%之銅呈銅（！【) 氧化態。 實施例6 :如本發明發明内容中所陳述之製備2,3•二氣吡 啶（1)之方法，其中銅觸媒中之銅（11)與3_胺基_2_氣吡啶（2) 之標稱莫耳比（亦即銅（π)之莫耳當量與3-胺基-2-氣吡啶之 莫耳數之比）為至少約〇.〇5。 實施例6Α :實施例6之方法，其中銅觸媒中之銅（11)與％ 胺基-2-氯》比啶（2)之標稱莫耳比為至少約〇 2。 實施例6Β :如本發明發明内容或實施例6至6八中任一實 施例中所陳述之製備2,3·二氣吡啶（1)之方法，其中銅觸媒 中之銅（II)與3·胺基_2_氯吡啶（2)之標稱莫耳比不超過約 2 〇 實施例6C :實施例6Β之方法，其中銅觸媒中之銅（π)與 138804.doc 200946504 3-胺基-2-氯吡啶（2)之標稱莫耳比不超過約〇6。 實施例7 :如本發明發明内容或實施例4至4入、5至5〇或 6至6C中任一實施例中所陳述之製備2,3•二氯吡啶（ι)之方 法’其中銅觸媒包含氣化銅（π)或氧化銅（11)。 實施例7A .實施例7之方法，其中銅觸媒包含氣化銅 (II) 〇 實施例8:如本發明發明内容中所陳述之製備2,3_二氣吼 啶（1)之方法，其中胺磺酸與相對於3_胺基_2_氣吡啶（2)過 量之亞硝酸鹽（亦即亞硝酸根離子之莫耳數）的標稱莫耳比 為至少約1。 實施例8A :實施例8之方法，其中胺磺酸與相對於弘胺 基-2-氯吡啶（2)過量之亞硝酸鹽的標稱莫耳比為至少約2。 貫施例8B :如本發明發明内容或實施例8至8八中任一實 施例中所陳述之製備2,3_二氣吡啶（1)之方法，其中胺磺酸 與相對於3-胺基-2-氯吡啶（2)過量之亞硝酸鹽的標稱莫耳 比不超過約4.5。 實施例8C :實施例8B之方法，其中胺磺酸與相對於夂胺 基-2-氯吡啶（2)過量之亞硝酸鹽的標稱莫耳比不超過約 2.5。 實把例9 :如本發明發明内容中所陳述之製備2,3_二氣吡 啶（1)之方法，其中步驟（1)係在至少約_15t：之溫度下進 行。 實施例9A :實施例9之方法，其中步驟（1)係在至少約_1(rc200946504 0·95. Embodiment 3A. The method of Embodiment 3 wherein the nominal molar ratio of the nitrite in step (2) to 3-amino-2-pyridine (2) is at least about i. Embodiment 3B. The method of Embodiment 3 wherein the nominal molar ratio of the nitrite in step (2) to 3-amino-2-pyridine (2) is at least about 1〇5. Embodiment 3C: A method for preparing 2,3-dichloro-(1), as described in any one of Examples 3 to 3B of the present invention, a nitrite and a 3-amino group in the step (7) The nominal molar ratio of 2-pyridine pyridine (2) (i.e., the ratio of the molar equivalent of the sulphate to the molar number of the 3-amino group m) does not exceed about 2. The method of Embodiment 3C, wherein the nominal molar ratio of the stannous acid salt in the step (7) to the 3-amine m (tetra) (2) is not exceeded. Embodiment 3E: A method for preparing 2 3 ---, 侑, j-a-pyridine (1) as recited in any one of the embodiments of the present invention or in any of embodiments 3 to 31), wherein the nitrite is sub- Sodium nitrate. Example 4: A method for preparing a 2,3-digastric bite (1) as recited in the Summary of the Invention, wherein the copper in the copper catalyst is equal to the nominal molar ratio of the amine to the amine (7) (ie, copper) The ratio of the molar equivalent to the molar amount of 3-amino-2_gas_ is at least about 〇.〇5. Example 4 A: Method of Example 4 The nominal molar ratio of the base-2-gas acridine (2) is 1 wherein the copper in the copper catalyst is at least about 0.2 with the 3-amine. Embodiment 4B: A method for preparing 2,3-dichloro(1) as described in the present invention or in any of Examples 4 to 4A, copper and 3 amine in a copper catalyst. The nominal molar ratio of 2_gas_(2) does not exceed about 2. 138804.doc 200946504 Embodiment 4C. The method of Embodiment 4B wherein the nominal molar ratio of copper in the copper catalyst to 3-amino-2-pyridine (2) does not exceed about 0.6. Embodiment 5: A method of preparing 2,3-dipyridyl (1) as recited in any one of embodiments of the present invention or any of embodiments 4 to 4 A, wherein at least about 75% of the copper is copper (II) ) oxidation state. Embodiment 5 A. The method of Embodiment 5 wherein at least about 90% of the copper is in a copper (II) oxidation state. Embodiment 5B. The method of Embodiment 5, wherein at least about 95% of the copper is in a copper (II) oxidation state. Embodiment 5C. The method of Embodiment 5B wherein at least about 99% of the copper is in a copper (ruthenium) oxidation state. Embodiment 5D The method of Embodiment 5C wherein about 1% copper is in a copper (![) oxidation state. Example 6: A method for preparing 2,3•di-pyridine (1) as recited in the Summary of the Invention, wherein copper (11) and 3-amino-2_pyridine in a copper catalyst (2) The nominal molar ratio (i.e., the ratio of the molar equivalent of copper (π) to the molar number of 3-amino-2-pyridine) is at least about 〇.〇5. Embodiment 6: The method of Embodiment 6, wherein the nominal molar ratio of copper (11) to % amino-2-chloro" to pyridine (2) in the copper catalyst is at least about 〇2. Embodiment 6: A method for producing 2,3·di-pyridine (1) as recited in the present invention or any one of Embodiments 6 to 68, wherein copper (II) in a copper catalyst is 3. The nominal molar ratio of the amine-2-chloropyridine (2) is not more than about 2 〇 Example 6C: The method of Example 6, wherein copper (π) and 138804.doc 200946504 3- in the copper catalyst The nominal molar ratio of the amino-2-chloropyridine (2) does not exceed about 〇6. Example 7: A method of preparing 2,3•dichloropyridine (1) as described in the present invention or in any of Examples 4 to 4, 5 to 5, or 6 to 6C The catalyst contains vaporized copper (π) or copper oxide (11). Embodiment 7A. The method of Embodiment 7, wherein the copper catalyst comprises vaporized copper (II) oxime Example 8: a method of preparing 2,3_dioxacridine (1) as set forth in the Summary of the Invention, The nominal molar ratio of the amine sulfonic acid to the excess of nitrite relative to the 3-amino-2-pyridine (2) (i.e., the molar number of nitrite ions) is at least about 1. Embodiment 8A. The method of Embodiment 8 wherein the nominal molar ratio of the amine sulfonic acid to the excess nitrite relative to the urethane-2-chloropyridine (2) is at least about 2. Example 8B: A method for preparing 2,3-dipyridine (1) as recited in the present invention or in any one of Examples 8 to 8 wherein the amine sulfonic acid is relative to the 3-amine The nominal molar ratio of the cumyl chloride (2) excess nitrite is no more than about 4.5. Embodiment 8C. The method of Embodiment 8B wherein the nominal molar ratio of the amine sulfonic acid to the excess nitrite relative to the guanamine-2-chloropyridine (2) does not exceed about 2.5. Example 9: A method of preparing 2,3_diqipyridine (1) as set forth in the Summary of the Invention, wherein step (1) is carried out at a temperature of at least about -15 t:. Embodiment 9A: The method of Embodiment 9, wherein step (1) is at least about _1 (rc)
之溫度下進行D 138804.doc 200946504 實施例9B :如本發明發明内容或實施例9至9 A中任一實 施例中所陳述之製備2,3-二氣吡啶（1)之方法，其中步驟（1) 係在不超過約45°C之溫度下進行。 實施例9C :實施例9B之方法，其中步驟（1)係在不超過 約20°C之溫度下進行。 實施例10 :如本發明發明内容中所陳述之製備2,3_二氣 。比"定（1)之方法’其中步驟〇係在至少約_15°c之溫度下進 行。 實施例1 0A :實施例1 〇之方法，其中步驟（2)係在至少 約-10 C之溫度下進行。 實施例10B :如本發明發明内容或實施例丨〇至i 〇A中任 實加例中所陳述之製備2,3-二氣α比咬（1)之方法，其中步 驟（2)係在不超過約2〇。〇之溫度下進行。 實施例10C :實施例1 〇B之方法，其中步驟（2)係在不超 過約10°C之溫度下進行。 實施例11 :如本發明發明内容中所陳述之製備2,3_二氣 吡啶（1)之方法’其中步驟（3)係在至少約3〇。〇之溫度下進 行。 實施例11A .實施例π之方法，其中步驟（3)係在至少約 5 0 C之溫度下進行。 實施例11B :如本發明發明内容或實施例丨丨至丨丨A中任 一實施例中所陳述之製備2,3_二氣D比啶（1)之方法，其中步 驟（3)係在不超過約9〇°C之溫度下進行。 實施例11C :實施例11B之方法，其中步驟（3)係在不超 138804.doc •10- 200946504 過約80°C之溫度下進行。 包括上述實施例1至UC以及本文中所述之任何其他實施 例的本發明之實施例可以任何方式組合。實施例⑴⑴之 組合例如為： • 實施例A :如本發明發明内容中所陳述之製備2,3-二氣 ."比咬⑴之方法，其中銅觸媒包含氯化銅（„)或氧化銅（11); 亞石肖酸鹽與3-胺基-2-氣吼咬⑺之標稱莫耳比為約〇·95至約 e 2’銅觸媒中之銅（II)與3-胺基-2-氯吡啶（2)之標稱莫耳比 為約0』5至'約2;料酸與相對於3_胺基_2-氯〇比咬（2)過量 之亞硝酸鹽之標稱莫耳比為約丨至約45丨步驟（1)中之鹽酸 與胺基-2-氣吼咬（2)之標稱莫耳比為約3至約1〇 ;且步驟 (3)中之鹽酸與3_胺基·2•氯„比咬（2)之標稱莫耳比為〇至約 10 ° 實施例B .實施例A之方法，其中亞石肖酸鹽與％胺基冬 氯°比咬（2)之標稱莫耳比為約〇·95至約Μ ;銅觸媒中之銅 φ (Π)與3_胺基氣吼嚏（2)之標稱莫耳比為約〇.2至約〇 6 ; 胺磺酸與相對於3_胺基_2_氯吡啶⑺過量之亞硝酸鹽之標 ， 稱莫耳比為約2至約2·5 ;步驟⑴中之鹽酸與3-胺基-2-氣》比 啶（2)之‘稱莫耳比為約3至約6 ;且步驟（3)中之鹽酸與％ 胺基-2-氣吡啶（2)之標稱莫耳比為約丨至約5。 實施例C .如本發明發明内容中所陳述之製備2,3-二氣 比疋⑴之方法’其中步驟⑴係在約-15°C至約45。(：範圍内 之皿度下進行；步驟（2)係在約-15°C至約2CTC範圍内之溫 度下進行，且步驟（3)係在約3〇°C至約90°C範圍内之溫度下 138804.doc 200946504 進行。 實施例D .實施例c之方法，其中步驟（丨）係在約_1〇〇c至 約25C範圍内之溫度下進行；步驟（2)係在約至約 ίοc範圍内之溫度下進行；且步驟係在約5(rc至約8〇〇c 範圍内之溫度下進行。 根據如流程1中所示之本發明之方法，藉由形成2_氯_3_ 胺基吼啶（2)之鹽酸鹽且隨後接著在胺磺酸及其中至少約 50%之銅呈銅（II)氧化態之銅（π)觸媒存在下分解氣化重氣 鹽，製備2,3-二氣^^(ι)。 流程1 aNH2 DHCl -^― ccD 138804.doc 200946504 Example 9B: A method of preparing 2,3-dioxapyridine (1) as set forth in any one of the embodiments of the present invention or any of Examples 9 to 9 A, wherein the step (1) It is carried out at a temperature not exceeding about 45 °C. Embodiment 9C: The method of Embodiment 9B wherein step (1) is carried out at a temperature not exceeding about 20 °C. Example 10: Preparation of 2,3_diox as set forth in the Summary of the Invention. The method of the method of (1) wherein the steps are carried out at a temperature of at least about -15 ° C. Embodiment 1 0A: The method of Example 1, wherein the step (2) is carried out at a temperature of at least about -10 C. Embodiment 10B: A method of preparing a 2,3-digas alpha ratio bite (1) as set forth in any of the embodiments of the present invention or an embodiment, wherein step (2) is No more than about 2 inches. It is carried out at a temperature of 〇. Embodiment 10C: The method of Embodiment 1 wherein the step (2) is carried out at a temperature not exceeding about 10 °C. Embodiment 11: A method of preparing 2,3-dipyridylpyridine (1) as set forth in the Summary of the Invention, wherein step (3) is at least about 3 Torr. Under the temperature of 〇. Embodiment 11A. The method of Embodiment π, wherein step (3) is carried out at a temperature of at least about 50 °C. Embodiment 11B: A method of preparing 2,3_digas D to pyridine (1) as set forth in any one of the embodiments of the present invention or an embodiment, wherein step (3) is Do not exceed a temperature of about 9 ° C. Embodiment 11C: The method of Embodiment 11B wherein step (3) is carried out at a temperature of not more than 138804.doc •10-200946504 at about 80 °C. Embodiments of the invention including the above-described embodiments 1 to UC and any other embodiments described herein may be combined in any manner. The combination of the embodiments (1) (1) is, for example: • Example A: A method for preparing 2,3-digas. "bite (1) as recited in the Summary of the Invention, wherein the copper catalyst comprises copper chloride („) or Copper oxide (11); the nominal molar ratio of sulphate and 3-amino-2-gasbite (7) is from about 〇95 to about e 2' copper catalyst (II) and 3 - Amino-2-chloropyridine (2) has a nominal molar ratio of from about 0"5 to about 2; the acid is more nitrite than the 3-amino-2-chloropurine (2) excess (2) The nominal molar ratio of the salt is from about 丨 to about 45 丨. The nominal molar ratio of hydrochloric acid to the amine-2-gas sputum (2) in the step (1) is from about 3 to about 1 Torr; and the step ( 3) The nominal molar ratio of hydrochloric acid to 3-amino-2·chlorine to bite (2) is 〇 to about 10 °. Example B. The method of Example A, wherein sulphate and % The nominal molar ratio of the amine-based winter chloride to the bite (2) is about 〇·95 to about Μ; the copper φ (Π) and the 3_amine gas 吼嚏 (2) in the copper catalyst are nominally The ear ratio is from about 〇.2 to about ;6; the amine sulfonic acid is in excess with the nitrite relative to the 3-amino-2-chloropyridine (7), and the molar ratio is from about 2 to about 2.5; (1) The hydrochloric acid and 3-amino-2- gas are more than a molar ratio of from about 3 to about 6 with respect to the pyridine (2); and the hydrochloric acid and the amino-amino-2-pyridine in the step (3) (2) The nominal molar ratio is from about 丨 to about 5. Embodiment C. A method of preparing 2,3-diox to hydrazine (1) as set forth in the Summary of the Invention, wherein step (1) is at about -15 ° C to about 45. (: in the range of the degree; the step (2) is carried out at a temperature in the range of about -15 ° C to about 2 CTC, and the step (3) is in the range of about 3 ° C to about 90 ° C The temperature is 138804.doc 200946504. Embodiment D. The method of embodiment c, wherein the step (丨) is carried out at a temperature ranging from about 1 〇〇c to about 25 C; the step (2) is at about Performing at a temperature in the range of about ίοc; and the step is carried out at a temperature in the range of about 5 (rc to about 8 〇〇c). According to the method of the invention as shown in Scheme 1, by forming 2_chloro_ 3_ the hydrochloride of the amine acridine (2) and then decomposing the gasified heavy gas salt in the presence of the amine sulfonic acid and at least about 50% of the copper in the copper (II) oxidation state of the copper (π) catalyst, Prepare 2,3-digas^^(ι). Scheme 1 aNH2 DHCl -^― cc
I、 Cl 3)H2NS03HI, Cl 3) H2NS03H
Cu〇I)鹽 2 1 在本發月方法中’由3_胺基_2_氣吼咬（2)之氫氣酸鹽（或 者2述為錢鹽）製備錢鹽。藉由使3·胺基定或 l a 3胺基-2-氣吡啶之溶液與鹽酸（亦即溶解於水中之氣 化II)接觸’製備氫氣酸鹽。多種程序適用於製備3·胺基· 2氯th咬之氫氯酸鹽。舉例而言，可向鹽酸水溶液中添加 固體3-胺基·2·氣。比。定，或可向固體3_胺基_2_氣吼咬中添加 酸水"令液 < 者’可將3_胺基-2-氣吡啶於水不混溶或水 展冷/合劑中之溶液與鹽酸水溶液依任何添加順序混合。最 宜向固體3-脸其, 胺丞-2-氣咐*啶中添加鹽酸水溶液來形成3_胺 基2-氣吡啶之氫氣酸鹽水溶液。化學計量上每莫耳3_胺 138804.doc 200946504 基-2-氯咐啶需要至少丨莫耳（亦即莫耳當量）鹽酸（亦即溶解 於水中之氣化氫）來完全形成氫氯酸鹽。通常使用至少約3 莫耳當量之鹽酸，且該量通常不超過約1〇莫耳當量，且更 通常不超過約6莫耳當量。雖然該步驟中可使用較低濃度 ' 之氣化氫（HC1)水溶液，但氣化氫於水中之濃度在與3-胺 . 基氯吡啶接觸之前通常為至少約10重量百分比且可高達 約37重量百分比’ 37重量百分比係受氣化氣於水中之溶解 φ 度限制。可在寬溫度範圍内使3·胺基·2_1_與鹽酸接 觸。為方便起見’通常在約周圍溫度下使3_胺基_2氯吡啶 與鹽酸接觸。因為氫氣酸鹽之形成放熱，所以冷卻鹽酸可 為有利的，以便在約]代與价之間進行接觸’且更尤 其約-HTC與20。(：之間的溫度下接觸。雖然可先分終胺 基-2-氯吡啶之氫氯酸鹽(例如’藉由蒸發鹽酸及任何其他 溶劑）後再形成溶液以進行重氮化，但最方便作法為直接 在重氮化步驟中使用3_胺基_2_氣。比咬之氨氣酸鹽水溶液。 • Τ藉由在合適溫度下使3_胺基咬（2)之氫氯酸鹽 〃亞硝酸在水/合液中反應，製備氣化重氮鹽。可由亞硝酸 Μ及鹽酸#場產生亞硝酸。因為在鹽酸存在下形成亞石肖酸 僅需要亞碗酸根離子即可，所以有很多種亞确酸鹽可以使 -用。亞硝酸鹽之常見實例包括鹼金屬及鹼土金屬亞硝酸 鹽，諸如亞石肖酸鈉、亞硝酸卸或亞石肖酸弼。較佳亞頌酸鹽 為亞碗酸鈉，因為其可以低成本購得。雖然任何量之亞靖 酸鹽均將產生-定產率之產物，但通常每莫耳式2化合物 使用至少約0_95且更通常至少約4耳當量之亞石肖酸鹽（亦 138804.doc 200946504 即提供1莫耳亞硝酸根離子），以使得式2化合物完全重氮 化。因為亞瑣酸鹽之量總是無法精確量測，尤其在大規模 製造中，所以較佳為使用過量亞硝酸鹽，來確保式2化合 物完全重氮化。此外，當每莫耳式2化合物使用1莫耳當量 以上亞硝酸鹽時，基本上實現根據本發明在銅觸媒混合物 中包括胺績酸之益處。雖然可使用較大量之亞确酸鹽，但 通常添加不超過約2莫耳當量且更通常不超過約1.1莫耳當 量亞硝酸鹽來使式2化合物重氮化。關於如何製備重氮鹽 之參考文獻，參見 H. Zollinger, Jzo awe/ D/αζο Wiley-Interscience, New York, 1961 ； S. Patai, The Chemistry of Diazonium and Diazo Groups, Wiley, New York, 1978， 第 8、11 及 14章；及 H. Saunders及 R. L. M. Allen, Jrowaiz'c Diazo Compounds ，第 3 版，Edward Arnold, London, 1985。在本發明之方法之一實施例中，使包含3-胺基-2-氯 吡啶（2)之溶液與包含鹽酸之水溶液接觸，以形成3-胺基-2-氯吡啶鹽酸鹽之溶液。隨後使3-胺基-2-氣吡啶鹽酸鹽溶 液與包含亞瑣酸鹽之水溶液接觸，形成氯化重氮鹽。藉由 向3-胺基-2-氣吡啶（2)於HC1水溶液（亦即鹽酸）中之混合物 中添加亞硝酸鹽（例如，亞硝酸鈉）水溶液，使3-胺基-2-氯 吡啶鹽酸鹽重氮化。雖然該步驟中可使用較低濃度之HC1 水溶液，但HC1之濃度在向水性反應混合物中添加其他組 分之前通常為至少約10%且可高達約37%，37%係受氣化 氫於水中之溶解度限制。本發明方法之該等步驟之其他實 施例係如上所述。 138804.doc -14- 200946504 為形成2,3-二氣吡啶（1)，在鹽酸、胺磺酸及其中至少約 50%之銅呈銅（II)氧化態之銅觸媒存在下分解氯化重氮鹽。 在其他實施例中，至少約75%、至少約90%、至少約 95%、至少約99%或100%之銅呈銅（II)氧化態。因為咸信 與氯配位體錯合之Cu+2離子（亦即，銅（II))為含有鹽酸之分 解水溶液中之催化物質，所以可添加寬範圍之銅鹽及其他 化合物作為銅觸媒。當銅觸媒溶解於分解水溶液中時，銅 觸媒通常溶解於水中且尤其鹽酸中。然而，儘管如此可使 用諸如氧化銅（II)之不溶於水之銅化合物作為觸媒，因為 其一經與鹽酸接觸即轉化為可溶性氯化銅（II)。銅觸媒可 包含例如（但不限於）乙酸銅（II)、硝酸銅（II)、硫酸銅（II)、 氧化銅（II)或氣化銅（II)。在一實施例中，銅觸媒包含氧化 銅（II)、氣化銅（II)或由CuO及鹽酸當場產生之氣化銅（II)。 在其他實施例中，至少75%之銅為氯化銅（II);至少90%之 銅為氯化銅（II);至少99%之銅為氯化銅（II);至少99%之 銅為氯化銅（II); 100%之銅為氯化銅（II);至少75%之銅為 氧化銅（II);至少90%之銅為氧化銅（II);至少95%之銅為 氧化銅（II);至少99%之銅為氧化銅（II);且100%之銅為氧 化銅（II)。 分解係在可為單一液相或者一個兩相系統之液相之水溶 液中進行。分解水溶液通常由至多約10莫耳當量、更通常 約1至約5莫耳當量呈通常約10%至約37%鹽酸水溶液形式 之HC1(相對於起始3-胺基-2-氯吡啶（2))起始。 雖然可在分解水溶液中包括寬範圍之量之銅觸媒，但通 138804.doc •15· 200946504 吊使用相對於起始3_胺基_2je比咬⑺至少約0.05莫耳當量 之鋼觸媒（尤其Cu(II))獲得有效反應速率。更通常使用至 =約〇.2莫耳當量之鋼觸媒（尤其Cu(II))獲得快速反應速 率。雖然可使用大量銅觸媒，但此增加成本及廢物處理。 利用約2莫耳當量以上之銅觸媒（尤其Cu(II))通常不見優 勢，且作為觸媒，所使用之量通常小於丨莫耳當量。銅觸 媒（尤其Cu(II))之量通常不超過約〇 6莫耳當量。 根據本發明之改良方法，在分解水溶液中包括胺續酸 (呈h2nso3h形式）。值得注意的是已發現胺績酸不干擾开) 成式1化合物之分解反應。雖然、可在添加重氮鹽溶液期 間，同時或分數份添加胺磺酸，但最方便的是在開始添加 重氮鹽溶液之前在分解溶液中添加所有胺磺酸。若在添加 重氮鹽溶液期間同時添加胺磺酸，則在分解水溶液中維持 足置胺磺酸來清除所添加之重氮鹽溶液中之過量亞硝酸時 獲得最佳結果。咸信胺磺酸與亞硝酸之清除反應之化學計 量是等莫耳的。雖然、任何量之胺續酸均有助於阻止由過量 亞硝酸引起之觸媒失活，但清除所有過量亞石肖酸需要每莫 耳當量超過式2化合物之亞硝酸鹽至少約〗莫耳胺磺酸。因 為過量胺磺酸除增加成本外幾乎沒有缺點，所以通常使用 每莫耳當量超過式2化合物的亞硝酸鹽至少約2莫耳胺磺 酸。使用每莫耳當量超過式2化合物的亞硝酸鹽通常不超 過約4.5莫耳、更通常不超過約2.5莫耳的胺磺酸。 添加重氮鹽溶液期間分解水溶液之溫度通常係維持在約 4〇°C至約9〇t範圍内。更通常，分解溫度係維持在約5〇1 138804.doc • 16 - 200946504 至約80°C範圍内’此提供方便的反應速率且得到高產率。 雖然實現該等溫度可忐需要外部加熱分解水溶液，但因為 分解係放熱的，所以尤其對大規模製備而言，可能需要冷 卻。 • 若分解利用單一液相進行，則可藉由使反應混合物冷卻 . 至周圍（例如i5_30°c)溫度，視情況添加鹼以中和反應混合 物且隨後藉由過濾收集固體產物來分離2,3_二氣吡啶（1)產 物。 ❹ 蒸汽蒸餾尤其便於自大規模製備反應混合物中分離2,3_ 二氯吡啶（1)。對於該分離方法，將蒸汽（通常在約大氣壓 下）注入經中和之反應混合物中。在約8(rc下，將所得鶴 份冷凝成基本上由2,3-二氣吡啶及水之混合物組成的液體 混合物。將液體冷凝混合物添加至維持在約丨5_25它下之 水中，從而引起2,3-二氣吡啶結晶。隨後藉由過濾所得漿 液來分離2,3-二氣吼咬產物。 〇 如早已提及，分解亦可利用包含合適有機溶劑以及單相 系統水溶液之兩相系統進行。為合適起見，有機溶劑僅需 要不可與水混溶（以形成兩相系統）且對反應條件呈惰性。 因此’非常多之有機溶劑為合適的。常見的合適有機溶劑 • 之實例包括諸如四氫呋喃之醚類；諸如環己烷、苯及甲苯 之烴類；諸如1-氣丁烷之齒代烴類；及諸如乙酸乙酯之酯 類。兩相系統中有機相與水相之體積比通常在約1:1〇至約 W.i範圍内。兩相系統中之產物2,3_二氯吡啶（j)可藉由用 水或鹼水溶液稀釋反應物質、相分離及濃縮有機相至乾來 13S804.doc -17- 200946504 · 刀離。亦可藉由結晶自有機相分離2,3-二氣吡啶（i)產物。 、’’σ 了藉由視情況在添加諸如庚烧或水之「反溶劑 (antisolvent)」下部分濃縮有機溶液來實現。術語「反溶 劑」意謂當添加至所需產物之溶液中時降低產物於所得混 合物中之溶解度的液體稀釋劑。因此，若溶劑為諸如醯胺 (例如，N，N-二甲基曱醯胺）或低級醇（例如，乙醇）之極性 /合劑，則可使用水作為反溶劑。另一方面，若溶劑為諸如 乙酸乙酯或二氣甲烷之適度非極性溶劑，則可使用諸如烴 (例如，環己烷或庚烷）之非極性溶劑作為反溶劑。用本發 明方法’由純3-胺基-2-氣吡啶（2)起始，2,3_二氣吡啶 (1)(純度為約98%)之分離產率可高達9〇_95%。相分離之水 相可視情況在部分濃縮後直接再循環至後續分解批料中以 重新使用Cu(II)鹽觸媒及過量鹽酸。 根據流程2中所示之多步方法，可藉由氣化3_胺基吡啶 (3)接著使所得2-氣-3-胺基。比啶（2)中間體重氮化且在胺磺 酸存在下分解氣化重氮鹽製備2,3-二氣吼啶（1)。 流程2 aNH2 DHC1 —雖'j > (ι 2重氮化_^Cu〇I) Salt 2 1 In the present method, a money salt is prepared from a 3-hydrocarbyl-2-indene (2) hydrogenate (or 2 as a money salt). The hydrogenation acid salt is prepared by contacting a solution of 3·amine or 1 a 3 amino-2-pyridine with hydrochloric acid (i.e., vaporized II dissolved in water). A variety of procedures are available for the preparation of the 3-amino-2 chloride thawed hydrochloride. For example, a solid 3-amino-2 gas can be added to an aqueous hydrochloric acid solution. ratio. Or, can add acid water to the solid 3_amine 2_ gas bite " ordering liquid < can '3' amine-2-pyridine in water immiscible or water-cooling / mixture The solution in solution is mixed with aqueous hydrochloric acid in any order of addition. Preferably, an aqueous solution of hydrochloric acid is added to the solid 3-faced, amidoxime-2-gas oxime* pyridine to form an aqueous solution of 3-amino-2-pyridinium hydrochloride. Stoichiometrically per mole 3_amine 138804.doc 200946504 -2-chloroacridine requires at least 丨 molar (ie, molar equivalent) hydrochloric acid (ie, hydrogenated hydrogen dissolved in water) to completely form hydrochloric acid salt. Typically at least about 3 moles of hydrochloric acid is used, and the amount typically does not exceed about 1 mole equivalent, and more typically does not exceed about 6 mole equivalents. Although a lower concentration of a vaporized hydrogen (HC1) aqueous solution can be used in this step, the concentration of vaporized hydrogen in water is typically at least about 10 weight percent and can be as high as about 37 prior to contact with the 3-amine chloropyridine. The weight percentage '37 weight percent is limited by the solubility φ of the gasification gas in the water. The 3·amino group·2_1_ can be contacted with hydrochloric acid over a wide temperature range. For convenience, the 3-amino-2-chloropyridine is usually contacted with hydrochloric acid at about ambient temperature. Since the formation of the hydrochloride salt is exothermic, it may be advantageous to cool the hydrochloric acid so as to make a contact between about valence and valence, and more particularly about -HTC and 20. (: Contact at a temperature between the two. Although it is possible to first dilute the amine of the amino-2-chloropyridine (for example, 'by evaporation of hydrochloric acid and any other solvent) and then form a solution for diazotization, but most It is convenient to use 3_amine 2_ gas directly in the diazotization step. It is a bit of ammonia aqueous solution. • 氢 Hydrochloric acid by biting (3) at a suitable temperature The hydrazine nitrite is reacted in water/liquid to prepare a gasified diazonium salt. The nitrous acid can be produced from the yttrium nitrite and hydrochloric acid fields. Because the formation of yttrium acid in the presence of hydrochloric acid only requires the sub-bate ion. Therefore, there are many kinds of sulfites which can be used. Common examples of nitrites include alkali metal and alkaline earth metal nitrites, such as sodium succinate, nitrous acid or yttrium succinate. The acid salt is sodium catenate because it is commercially available at low cost. While any amount of the benzoic acid salt will produce a product of a constant yield, it will generally be at least about 0-95 and more usually at least about every mole of the compound of the formula 2 About 4 ears equivalent of sulphate (also 138804.doc 200946504 provides 1 mol of nitric acid Root ion), so that the compound of formula 2 is completely diazotized. Since the amount of succinic acid salt is always not accurately measured, especially in large-scale manufacturing, it is preferred to use an excess of nitrite to ensure the compound of formula 2 Complete diazotization. In addition, when 1 mole equivalent or more of nitrite is used per mole of the compound of the formula 2, the benefit of including the amine acid in the copper catalyst mixture according to the present invention is substantially achieved. The acid salt, but typically no more than about 2 mole equivalents and more typically no more than about 1.1 moles of nitrite is added to diazotize the compound of formula 2. For a reference on how to prepare a diazonium salt, see H. Zollinger, Jzo awe/ D/αζο Wiley-Interscience, New York, 1961 ; S. Patai, The Chemistry of Diazonium and Diazo Groups, Wiley, New York, 1978, Chapters 8, 11 and 14; and H. Saunders and RLM Allen, Jrowaiz'c Diazo Compounds, 3rd edition, Edward Arnold, London, 1985. In one embodiment of the method of the invention, a solution comprising 3-amino-2-chloropyridine (2) is formulated with hydrochloric acid. Aqueous solution contact To form a solution of 3-amino-2-chloropyridine hydrochloride. The 3-amino-2-pyridinium hydrochloride solution is then contacted with an aqueous solution containing a succinic acid salt to form a chlorinated diazonium salt. Adding an aqueous solution of nitrite (for example, sodium nitrite) to a mixture of 3-amino-2-pyridinium (2) in an aqueous solution of HCl (ie, hydrochloric acid) to give 3-amino-2-chloropyridinium salt The acid salt is diazotized. Although a lower concentration of aqueous HCl solution can be used in this step, the concentration of HCl is typically at least about 10% and up to about 37% prior to the addition of other components to the aqueous reaction mixture, 37% being hydrogenated in water. Solubility limit. Other embodiments of the steps of the method of the invention are as described above. 138804.doc -14- 200946504 To form 2,3-dioxapyridine (1), decompose chlorination in the presence of hydrochloric acid, amine sulfonic acid and at least about 50% of copper in the copper (II) oxidation state of copper catalyst Diazonium salt. In other embodiments, at least about 75%, at least about 90%, at least about 95%, at least about 99%, or 100% of the copper is in a copper (II) oxidation state. Because the Cu+2 ion (ie, copper(II)), which is a mixture of the salt and the chlorine ligand, is a catalytic substance in the aqueous solution containing hydrochloric acid, a wide range of copper salts and other compounds can be added as a copper catalyst. . When the copper catalyst is dissolved in the aqueous decomposition solution, the copper catalyst is usually dissolved in water and especially in hydrochloric acid. However, in spite of this, a water-insoluble copper compound such as copper (II) oxide can be used as a catalyst because it is converted into soluble copper (II) chloride upon contact with hydrochloric acid. The copper catalyst may comprise, for example, but not limited to, copper (II) acetate, copper (II) nitrate, copper (II) sulfate, copper (II) oxide or copper (II) vapor. In one embodiment, the copper catalyst comprises copper (II) oxide, copper (II) vaporized or vaporized copper (II) produced on the spot by CuO and hydrochloric acid. In other embodiments, at least 75% of the copper is copper (II) chloride; at least 90% of the copper is copper (II) chloride; at least 99% of the copper is copper (II) chloride; at least 99% copper It is copper (II) chloride; 100% copper is copper (II) chloride; at least 75% copper is copper (II) oxide; at least 90% copper is copper (II) oxide; at least 95% copper is Copper (II) oxide; at least 99% of the copper is copper (II) oxide; and 100% of the copper is copper (II) oxide. The decomposition is carried out in an aqueous solution which can be a single liquid phase or a liquid phase of a two-phase system. The aqueous decomposition solution typically has from about 10 mole equivalents, more typically from about 1 to about 5 mole equivalents, of HCl in the form of typically from about 10% to about 37% aqueous hydrochloric acid (relative to the starting 3-amino-2-chloropyridine ( 2)) Start. Although a wide range of copper catalysts can be included in the aqueous decomposition solution, the 138804.doc •15·200946504 suspension uses at least about 0.05 moles of steel catalyst relative to the starting 3_amine 2je to bite (7). (especially Cu(II)) obtains an effective reaction rate. It is more common to use a steel catalyst (especially Cu(II)) up to about 2.2 mole equivalent to obtain a fast reaction rate. Although a large amount of copper catalyst can be used, this increases cost and waste disposal. Copper catalysts (especially Cu(II)) of about 2 mole equivalents or more are generally not used, and as a catalyst, the amount used is usually less than the molar equivalent. The amount of copper catalyst (especially Cu(II)) typically does not exceed about 6 mole equivalents. According to an improved process of the invention, an amine acid (in the form of h2nso3h) is included in the aqueous decomposition solution. It is noteworthy that it has been found that the amine acid does not interfere with the decomposition reaction of the compound of formula 1. Although it is possible to add the amine sulfonic acid at the same time or in portions during the addition of the diazonium salt solution, it is most convenient to add all the amine sulfonic acid to the decomposition solution before starting the addition of the diazonium salt solution. If the aminesulfonic acid is added simultaneously during the addition of the diazonium salt solution, the best results are obtained by maintaining the foot aminesulfonic acid in the aqueous decomposition solution to remove excess nitrous acid in the added diazonium salt solution. The stoichiometric reaction of the salty amine sulfonic acid with nitrous acid is equimolar. Although any amount of amine acid continues to help prevent catalyst deactivation by excess nitrous acid, removal of all excess succinic acid requires at least about moles of nitrite per mole equivalent of the compound of formula 2. Amine sulfonic acid. Since excess amine sulfonic acid has few disadvantages in addition to increased cost, it is common to use at least about 2 moles of sulfite per mole equivalent of the nitrite of the compound of formula 2. The nitrite used in excess of the compound of formula 2 per mole equivalent typically does not exceed about 4.5 moles, and more typically does not exceed about 2.5 moles of amine sulfonic acid. The temperature at which the aqueous solution is decomposed during the addition of the diazonium salt solution is usually maintained in the range of from about 4 ° C to about 9 Torr. More typically, the decomposition temperature is maintained in the range of about 5 〇 1 138804.doc • 16 - 200946504 to about 80 ° C. This provides a convenient reaction rate and a high yield. Although achieving such temperatures may require external heating to decompose the aqueous solution, because the decomposition is exothermic, especially for large scale production, cooling may be required. • If the decomposition is carried out using a single liquid phase, the reaction mixture can be cooled by heating the reaction mixture to ambient (eg i5_30 °c), optionally adding a base to neutralize the reaction mixture and then collecting the solid product by filtration. _ Digas pyridine (1) product.蒸汽 Steam distillation is particularly convenient for the separation of 2,3-dichloropyridine (1) from large-scale preparation of the reaction mixture. For this separation process, steam (usually at about atmospheric pressure) is injected into the neutralized reaction mixture. The resulting crane fraction is condensed to a liquid mixture consisting essentially of a mixture of 2,3-dipyridine and water at about 8 (rc). The liquid condensation mixture is added to the water maintained under about 5-25, causing Crystallization of 2,3-dioxapyridine. The 2,3-diox bite product is then separated by filtration of the resulting slurry. As already mentioned, the decomposition can also utilize a two-phase system comprising a suitable organic solvent and an aqueous solution of a single phase system. For the sake of suitability, the organic solvent only needs to be immiscible with water (to form a two-phase system) and is inert to the reaction conditions. Therefore, 'a lot of organic solvents are suitable. Examples of common suitable organic solvents include Ethers such as tetrahydrofuran; hydrocarbons such as cyclohexane, benzene and toluene; toothed hydrocarbons such as 1-gasbutane; and esters such as ethyl acetate. Volume of organic phase and aqueous phase in a two-phase system The ratio is usually in the range of about 1:1 Torr to about Wi. The product in the two-phase system, 2,3-dichloropyridine (j), can be diluted with water or an aqueous alkali solution, phase separated, and the organic phase is concentrated to dryness. 13S804.doc -17- 2009465 04 · Knife separation. It is also possible to separate the 2,3-dipyridine (i) product from the organic phase by crystallization. , ''σ by adding an antisolvent such as heptane or water as appropriate. The lower portion is concentrated with an organic solution. The term "antisolvent" means a liquid diluent that reduces the solubility of the product in the resulting mixture when added to a solution of the desired product. Thus, if the solvent is such as a guanamine (eg, N) , N-dimethyl decylamine) or a lower alcohol (for example, ethanol) polarity / mixture, water can be used as an anti-solvent. On the other hand, if the solvent is moderately non-polar such as ethyl acetate or di-methane As the solvent, a non-polar solvent such as a hydrocarbon (for example, cyclohexane or heptane) can be used as an anti-solvent. Starting from pure 3-amino-2-pyridine (2) by the method of the present invention, 2, 3 The isolated yield of bis-dipyridine (1) (purity of about 98%) can be as high as 9〇_95%. The phase-separated aqueous phase can be directly recycled to the subsequent decomposition batch after partial concentration to reuse Cu. (II) salt catalyst and excess hydrochloric acid. According to the multi-step method shown in the scheme 2, The 3-aminopyridine (3) is then subjected to the resulting 2-oxa-3-amino group. The intermediate is diazotized with the pyridine (2) intermediate and the gasified diazonium salt is decomposed in the presence of an amine sulfonic acid to prepare 2,3-dialdehyde. Acridine (1). Process 2 aNH2 DHC1 - although 'j > (ι 2 diazotization _^
、人Cl 3)H2NS03H c_鹽 3 2 1 已報導藉由在70-80C之溫度下使3 -胺基D比咬（3)與鹽酸 及過氧化虱反應製備3-胺基-2-氣吼咬（2)(0. von Schickh, A. Binz，and A. Schultz, C/ie/w· Ber·，1936，（59，2593)。該 138804.doc 200946504 ^ Yuan ^ A (Zhongguo Yiyao Gongye Zazhi, 2000, 37，420)優化以藉由將反應溫度降低至20-30°C且利用1莫 耳當量15重量百分比過氧化氫及濃HC1水溶液（約37重量百 分比）作為氯化劑使過度氯化產物之量降至8重量百分比。 亦已報導由過渡金屬催化氯化3-胺基吡啶（3)製備3-胺 基-2-氣吡啶（2)(Blank等人，US 3,838，136)。該方法雖然在 生產規模下提供較上述von Schickh方法佳之產率，但具有 需要有害物質（氣）、產物以相對不純之形式（約87重量百分 比）呈固體而分離且金屬觸媒不易再循環，從而潛在引起 廢物處理問題的缺點。K. Ieno於JP 09227522中描述了由 Blank等人之方法製備之3-胺基-2-氯吡啶（2)自副產物3-胺 基-2，6 -二氣Dtt咬的純化。 R. Shapiro 於 WO 2005/070888 中描述了自 3-胺基吡啶（3) 產生較高品質之3-胺基-2-氯吡啶（2)的更具選擇性的氣化 方法。使用高濃度過氧化氫（約20重量百分比至約50重量 百分比）、濃HC1及低溫（約10°C至約35°C)使過度氣化之產 物（基本上為3-胺基-2,6-二氯吡啶）最少化。此外，藉由利 用氫氧化鈉代替NH3將反應混合物之pH值調節至約0.4接著 用二氣乙烷代替曱苯萃取之對Ieno方法的修改使得3-胺基-2-氯吡啶（2)易於純化且形成不求助於重結晶及過濾即適於 重氮化步驟之3-胺基-2-氣吡啶（2)鹽酸鹽。由該改良方法 可獲得約70%至約80%之反應產率，其中3-胺基吡啶（3)之 轉化率超過90%。 R. Shapiro亦於WO 2005/070888中描述了無須分離中間 138804.doc -19- 200946504 體固體之製備2,3-二氣吡啶（1)之方法。流程3描繪該根據 本發明藉由在使3-胺基吼啶（3)轉化為2,3_二氣吼啶（1)中包 括胺磺酸及含CU(II)觸媒改良之方法。該改良方法因此包 括菸醯胺（4)霍夫曼重排（H〇fmann rearrangement)以形成3_ 胺基》比啶（3)，用合適氯化劑選擇性氯化3_胺基吼啶（3)， 使2-氣-3-胺基吡啶（2)重氮化及在胺磺酸存在下用其中至 少約50。/。之銅呈銅（Π)氧化態之銅觸媒分解氣化重氮鹽。 流程3, human Cl 3) H2NS03H c_salt 3 2 1 has been reported to prepare 3-amino-2- gas by reacting 3-amino D with bite (3) with hydrochloric acid and barium peroxide at a temperature of 70-80C. Bite (2) (0. von Schickh, A. Binz, and A. Schultz, C/ie/w. Ber., 1936, (59, 2593). The 138804.doc 200946504 ^ Yuan ^ A (Zhongguo Yiyao Gongye Zazhi, 2000, 37, 420) optimized to reduce excess reaction temperature by 20-30 ° C and using 1 molar equivalent of 15 weight percent hydrogen peroxide and concentrated HCl aqueous solution (about 37 weight percent) as chlorinating agent The amount of chlorinated product is reduced to 8 weight percent. It has also been reported that 3-amino-2-pyridine (2) is prepared by transition metal catalyzed chlorination of 3-aminopyridine (3) (Blank et al., US 3,838,136 Although the method provides a better yield than the above-mentioned von Schickh method at the production scale, it requires a harmful substance (gas), the product is separated as a solid in a relatively impure form (about 87% by weight), and the metal catalyst is not easy to be used again. Cycling, which potentially causes a disadvantage of waste disposal problems. K. Ieno describes in the method of Blank et al. Purification of the base 2-chloropyridine (2) from the by-product 3-amino-2,6-diox Dtt bit. R. Shapiro describes the production of 3-aminopyridine (3) from WO 2005/070888 A more selective gasification process for high quality 3-amino-2-chloropyridine (2) using high concentrations of hydrogen peroxide (about 20 weight percent to about 50 weight percent), concentrated HC1 and low temperature (about 10 °C to about 35 ° C) minimizes the over-gasified product (essentially 3-amino-2,6-dichloropyridine). In addition, the pH of the reaction mixture is replaced by sodium hydroxide instead of NH3. Modification to about 0.4 followed by dioxane instead of hydrazine extraction. The modification of the Ieno process allows 3-amino-2-chloropyridine (2) to be easily purified and formed without re-crystallization and filtration for diazotization. Step 3-Amino-2-pyridinium (2) hydrochloride. A reaction yield of from about 70% to about 80% can be obtained by the modified process, wherein the conversion of 3-aminopyridine (3) exceeds 90. R. Shapiro also describes in WO 2005/070888 a method for the preparation of 2,3-dioxapyridine (1) without the separation of intermediate solids 138804.doc -19- 200946504. Scheme 3 depicts the invention according to the invention A method for improving amine sulfonic acid and CU(II)-containing catalyst by converting 3-aminopyridinium (3) to 2,3-dioxidine (1). The improved process thus includes the nicotinamide (4) H〇fmann rearrangement to form the 3-aminol-pyridyl (3), which is selectively chlorinated with a suitable chlorinating agent. 3), diazotizing 2-ox-3-aminopyridine (2) and using at least about 50 thereof in the presence of an amine sulfonic acid. /. The copper is in the form of copper (Π) oxidized copper catalyst to decompose the gasified diazonium salt. Process 3
1) 氣化劑 2) HC1 3) 重氮化 4) H2NS03H Cu(II)鹽1) Gasification agent 2) HC1 3) Diazotization 4) H2NS03H Cu(II) salt
咸信利用前述說明熟習此項技術者可最大程度地利用本 發明。因此，應將下列實例理解為僅說明性的且無論如何 不應理解為揭示内容之限制。除非另作說明，否則百分比 係以重量計。產物之定量HPLC係利用Zorbax Eclipse XDB-C8® 預填充層析柱（由 Agilent Techn〇l〇gies，Pal〇 Aho, CA 94303製造之逆相柱）（粒度為3 μιη，4 6 mmxi5 cm’溶離劑為含〇·〇5%三氟乙酸之ι5_95%乙腈/水）執行。 對照實例1 製備2,3-二氣吡啶（1) 在該實例中，使用7%莫耳過量亞硝酸鈉使3_胺基_2_氣 D比啶（2)重氮化，使重氮鹽溶液中之殘餘亞硝酸與銅觸媒接 觸。在存在或不存在胺磺酸之情況下使數份該重氮鹽溶液 138804.doc -20· 200946504 與銅觸媒接觸以評估根據本發明方法包括胺磺酸之效應。 向配備有溫度計、加料漏斗及氮氣入口之丨1反應器中 裝入52.2 g(0.4〇 mol)商業級3胺基_2_氣吡啶（2)及32〇 g(l.75 mol，4.35當量）20¾ HC1水溶液，同時將溫度維持 . 在約15 C下。將混合物冷卻至5。(：後，在5至1〇。(：下經30分 , 鐘添加30·4 g(0.428 mmol，1.07當量）亞硝酸鈉於60 g水中 之溶液。使混合物在5。〇下攪拌15分鐘。隨後將重氮鹽溶 ❿ 液分成2等份（每份232 g)。在進行以下程序A&B之前將兩 份重氮鹽溶液維持在5。〇下。 程序A(無胺磺酸）： 將以上所製備之重氮鹽溶液的一半經30分鐘泵送至 10.23 g(60 mmol，〇3〇 當量）二水合氯化銅（π)於 6〇〇 g(〇_325 mol)20% HC1水溶液中之溶液中，同時將反應溫度 維持在55-62。(：下且用油鼓泡器定性監測氮氣析出。氣體 釋放在添加後約5分鐘起始（自劇烈氣體釋放及發泡開始）且 © #添加完成後幾乎立即終止。值得注意的事實是添加期間 反應溫度開始下降且必須增加熱量輸入來將反應溫度維持 在55°C與62°C之間，從而顯示觸媒已失活。 程序B(存在胺磺酸）： 將另一半重氮鹽溶液經3〇分鐘泵送至10.23 g(60 mmol， 〇·30當量）二水合氣化銅（II)及2.72 g(28 mmo卜每莫耳過量 亞硝馱鹽2莫耳）胺磺酸於60.0 g(0.325 mol)20% HC1水溶液 中之'合液中，同時將反應溫度維持在55-62°C下且用油鼓 器定!·生现測氮氣析出。值得注意的事實是未觀察到氣體 138804.doc 200946504 釋放延遲且添加期間反應溫度開始上升且必須關閉熱量輸 入來將反應溫度保持在55°C與62°C之間，從而顯示觸媒尚 未失活。 使該兩種反應混合物冷卻至室溫且隨後添加37% HC1水 溶液直至固體溶解（程序B因產物含量較高而需要更多的 酸）。鹽酸添加完成後，程序A之溶液重377 g，而程序B之 溶液因需要額外的酸溶解固體而重436 g。由相對於外標 的HPLC重量百分比分析檢定溶液之3-胺基-2-氣吡啶（2)及 2,3-二氯吡啶（1)，且結果展示於下表A中。The present invention can be utilized to the fullest extent by those skilled in the art using the foregoing description. Therefore, the following examples should be construed as illustrative only and should not be construed as limiting the disclosure. The percentages are by weight unless otherwise stated. Quantitative HPLC of the product was performed using a Zorbax Eclipse XDB-C8® pre-packed column (reverse phase column manufactured by Agilent Techn〇l〇gies, Pal〇Aho, CA 94303) (particle size 3 μιη, 4 6 mm xi5 cm 'dissolution) The agent was carried out for ι5_95% acetonitrile/water containing 〇·〇 5% trifluoroacetic acid. Comparative Example 1 Preparation of 2,3-dioxapyridine (1) In this example, 3-aminol-2-gas D was diazotized with pyridine (2) using 7% molar excess of sodium nitrite to make diazo The residual nitrous acid in the salt solution is contacted with a copper catalyst. Several portions of the diazonium salt solution 138804.doc-20.200946504 were contacted with a copper catalyst in the presence or absence of amine sulfonic acid to evaluate the effect of the amine sulfonic acid included in the process according to the present invention. A reactor equipped with a thermometer, addition funnel and nitrogen inlet was charged with 52.2 g (0.4 mmol) of commercial grade 3 amine base 2_pyridine (2) and 32 g (l.75 mol, 4.35 equivalents). ) 203⁄4 HC1 aqueous solution while maintaining the temperature. At about 15 C. The mixture was cooled to 5. (: After 5 to 1 〇. (: After 30 minutes, add 30. 4 g (0.428 mmol, 1.07 equivalent) of sodium nitrite in 60 g of water. Allow the mixture to stir for 15 minutes at 5. The diazonium salt solution was then divided into 2 equal portions (232 g each). Two diazonium salt solutions were maintained at 5. Before the following procedure A&B. Procedure A (amine-free sulfonic acid) : Half of the diazonium salt solution prepared above was pumped to 10.23 g (60 mmol, 3 〇 equivalent) of copper chloride dihydrate (π) at 6 〇〇g (〇_325 mol) 20% over 30 minutes. In the solution in the aqueous solution of HC1, the reaction temperature was maintained at 55-62 at the same time. (: and the nitrogen gas was qualitatively monitored by an oil bubbler. The gas release started about 5 minutes after the addition (from the intense gas release and foaming) And the ## addition is almost immediately terminated after completion. It is worth noting that the reaction temperature begins to decrease during the addition and heat input must be increased to maintain the reaction temperature between 55 ° C and 62 ° C, indicating that the catalyst has been deactivated Procedure B (in the presence of amine sulfonic acid): The other half of the diazonium salt solution was pumped to 10.23 g (60 mmol) over 3 Torr. , 〇·30 equivalents) of copper (II) dihydrate and 2.72 g (28 mmo per mole of excess nitrosonium salt 2 moles) of amine sulfonic acid in 60.0 g (0.325 mol) of 20% aqueous HCl solution In the liquid mixture, the reaction temperature is maintained at 55-62 ° C and the oil drum is used to determine the nitrogen evolution. It is worth noting that no gas is observed. 138804.doc 200946504 Release delay and reaction temperature during addition The rise began and the heat input must be turned off to maintain the reaction temperature between 55 ° C and 62 ° C, indicating that the catalyst has not been deactivated. The two reaction mixtures were allowed to cool to room temperature and then 37% aqueous HCl solution was added until solid Dissolved (Procedure B requires more acid due to higher product content). After the addition of hydrochloric acid, the solution of Procedure A weighs 377 g, while the solution of Procedure B weighs 436 g due to the need for additional acid to dissolve the solid. The HPLC weight percent analysis of the external standard assayed the solution of 3-amino-2-pyridine (2) and 2,3-dichloropyridine (1), and the results are shown in Table A below.
表A 程序 化合物2 2-氯-3-經基 化合物1 化合物1 化合物1 (wt %) 0比咬(wt %) (wt %) (wt g) 產率(％) A 0 2.94 3.60 13.58 46 B 0 0 6.43 28.02 95 表A中之結果展示根據本發明在重氮鹽分解期間存在胺 磺酸顯著提高2,3-二氯吡啶（1)之產率。 138804.doc 22-Table A Program Compound 2 2-Chloro-3-yl-based Compound 1 Compound 1 Compound 1 (wt%) 0-bite (wt%) (wt%) (wt g) Yield (%) A 0 2.94 3.60 13.58 46 B 0 0 6.43 28.02 95 The results in Table A show the presence of amine sulfonic acid during the decomposition of the diazonium salt according to the invention to significantly increase the yield of 2,3-dichloropyridine (1). 138804.doc 22-
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